1. Field of the Invention
The present invention is in the fields of pharmaceuticals, formulations chemistry and pharmacology. The invention generally relates to compositions comprising azelastine or pharmaceutically acceptable salts or esters thereof, including azelastine hydrochloride. In certain embodiments, the invention provides pharmaceutical compositions comprising azelastine hydrochloride formulated for use as nasal sprays and/or ocular solutions or drops, as well as dosage formulations for oral and pulmonary delivery. The invention also relates to pharmaceutical compositions comprising one or more active pharmaceutical ingredients, including antihistamines such as azelastine or pharmaceutically acceptable salts or esters thereof, for example, azelastine hydrochloride, particularly wherein the compositions are provided in unit dosage form. In certain embodiments, the invention provides such unit dosage pharmaceutical compositions comprising antihistamines such as azelastine hydrochloride formulated for use as nasal sprays and/or ocular or otic solutions or drops. The invention also relates to methods of use of such compositions in treating, alleviating or preventing symptoms associated with a variety of allergic and non-allergic conditions, particularly conjunctivitis and rhinitis.
2. Related Art
Azelastine is a second-generation H1 antagonist antihistamine which is used for its anti-allergic, anti-asthmatic and antihistamine properties. Azelastine is a phthalazinone derivative having the following structural formula:

Azelastine can be produced in a variety of salt forms. The form most frequently used in pharmaceuticals is azelastine hydrochloride, which occurs as a white, almost odorless, crystalline powder with a strong bitter taste. The chemical name for azelastine hydrochloride is (±)-1-(2H)-phthalazinone, 4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-, mono-hydrochloride and its molecular formula is C22H24ClN3O.HCl. Other salt forms suitable for use in pharmaceutical compositions include azelastine embonate, which is reduced in bitterness compared to azelastine HCl (see U.S. Pat. No. 5,232,919 the disclosure of which is incorporated herein by reference), but which may also be less effective than azelastine HCl.
Research has shown that azelastine and its physiologically acceptable salt forms exhibit beneficial effects when the corresponding formulations are applied directly onto the nasal mucosa and/or the conjunctival sac of the eye (see U.S. Pat. No. 5,164,194). Elimination of symptoms or noticeable relief has thus been achieved in allergic rhinitis (seasonal and/or nonseasonal), vasomotor rhinitis and allergic conjunctivitis.
Despite its effectiveness, azelastine hydrochloride possesses a strong bitter taste. This bitter taste is so intense that it was found to be unpleasant even at a dilution of 1×106 (see U.S. Pat. No. 5,164,194). The bitter taste was not thought to be a problem in intranasal delivery of azelastine hydrochloride (see id.). However, subsequent clinical studies have shown that the bitter taste of azelastine hydrochloride is, indeed, an undesired element as a portion of the medication usually drips down into the pharynx after intranasal administration leading to an unpleasant and undesired taste experience by the patient. For example, MedPointe Pharmaceuticals, Inc. (Somerset, N.J.) has reported in the ASTELIN® product label insert that in clinical studies, the bitter taste adverse event occurred statistically more often in patients treated with ASTELIN® brand Nasal Spray (containing 0.10% w/v azelastine hydrochloride) versus vehicle placebo (19.7% vs. 0.6%). Likewise, the fluid formed by a combination of an ocularly administered medication, and induced tears secreted by the lachrymal glands, drains via the nasolachrymal duct into the nose and ultimately down the pharynx (see Day, N., “Ophthalmic Dosage Forms,” in: Pharmaceutical Preformulation and Formulation, Buffalo Grove, Ill.: Interpharm Press (2002)). Such post-nasal drip caused by the ocular administration of compositions comprising azelastine hydrochloride therefore can also induce a bitter and unpleasant taste experience by the patient. Ukai et al. (U.S. Pat. No. 6,576,677) disclose the use of polyvinylpyrrolidone and/or copolyvidone to mask the taste of bitter medicaments, including azelastine.
Although the current conventional systems used for application of nasal or ocular pharmaceutical formulations have been shown to be clinically efficacious, they can suffer from relatively low efficiency levels in delivering pharmaceutical-containing solutions to the nasal mucosa or conjunctiva of a patient, thereby wasting a substantial portion of the pharmaceutical formulations and substantially increasing drug delivery costs. The low efficiency of current conventional delivery systems can also require patients to devote relatively long time periods or high volume of application of the formulations to receive an effective dose of the active pharmaceutical ingredient, which can lead to decreased patient compliance. Moreover, the use of preservatives in pharmaceutical formulations, often problematic for nasal or ocular medications due to the stinging of the nose or eye associated with the preservative, is nonetheless typically required so as to reduce or avoid bacterial contamination in multi-use conventional containers currently used for storage and application of nasal and ocular pharmaceutical formulations.
There remains a need for a therapeutically effective dose of azelastine hydrochloride, particularly for nasal, ocular, or pulmonary delivery, which possesses a more desired taste and/or has a reduced ability to drip down into the pharynx after intranasal or ocular administration, thus improving patient acceptability and compliance. Accordingly, there is also a need for new and improved methods and devices for the storage and delivery of pharmaceutical compositions, such as those comprising antihistamines including azelastine hydrochloride, particularly for nasal, ocular, otic or topical delivery, which will reduce administration costs, increase patient compliance, enhance overall effectiveness of the therapy and reduce or eliminate the need for including preservatives in the formulations.